This Case Gl SPORE proposal provides for a cutting edge Specialized Program of Research Excellence in gastrointestinal malignancies with emphasis on colorectal cancers and with additional attention to adenocarcinoma of the esophagus. This comprehensive program builds on the resources of the Case Comprehensive Cancer Center to propose 4 translational Research Projects to bring new molecular advances to patients with Gl Cancers. A series of 4 core resources support these research projects and also establish a strong programmatic infrastructure for translational research in Gl cancers. We further have developed a comprehensive infrastructure for identifying new Developmental Research Projects from basic science and clinical investigators from across the Case Cancer Center. Moreover, drawing on our strong track record of developing new faculty who emphasize translational research in Gl cancers, we propose a targeted Career Development Program to further enhance the translational research cadre of SPORE faculty. The 4 SPORE translational research projects constitute novel and cutting edge approaches to Gl cancers and include studies of: the predictive, prognostic, and therapeutic applications of the new 15-PGDH colon cancer suppressor pathway (Project 1, Drs. Markowitz and Willson); the noninvasive early detection of advanced colon adenomas through stool DNA testing for methylated DNA (Project 2, Drs. Cooper and Li); the comprehensive evaluation of colon cancer gene mutations as predictors of clinical outcome, via use of high throughput Next Generation genomic sequencing (Project 3, Drs. Willis and Wang); and the identification of esophageal adenocarcinoma susceptibility genes (Project 4, Drs. Chak and Elston). These projects are advantaged by special population and scientific resources developed by our SPORE faculty for: evaluation of colon cancer biomarkers, for high throughput screening for new drug discovery, for evaluation of colon cancer screening modalities, for Next Generation sequencing from archived formalin fixed tissue samples, and for study of familial Barrett's and adenocarcinomas of the esophagus. The strength of these investigators and the resources at their disposal will ensure this program leads to important advances.